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Background

Dose escalation has been shown in a number of prospective randomized trials to improved biochemical recurrence free survival for prostate cancer.

It has also been suggested that the ?/? ratio for prostate cancer is low at 1.5 Gy. Because of this, attempts have been made to take advantage of the low ?/? ratio using hypofractionation as a means of dose escalation. This method uses larger doses of radiation per fraction with fewer fractions total.

The authors undertook a randomized trial at Fox Chase Cancer Center to evaluate the use of hypofractionated radiation (2.7 Gy/fraction) versus conventional fractionation (2 Gy/ fraction). The authors have previously presented the acute toxicity from the trial on the first 100 patients in the Red Journal (IJROBP, 2006)

In that publication, they reported the hypofractionated arm was associated with slight increased acute GI toxicity within the first month, which was predicted by the rectal V65 Gy (volume of rectum receiving 65 Gy).

The authors hypothesized that using hypofractionation to deliver the equivalent of an 8 Gy difference in 2 Gy fractions would significantly improve biochemical failure (BF) without increasing bladder or rectal side effects. The trial compared 76 Gy in conventional 2.0 Gy fractions (Conventional IMRT) to 70.2 Gy in 2.7 Gy fractions (Hypofractionated IMRT), which was estimated to be equivalent to 84.4 Gy in 2.0 Gy fractions.

Materials and Methods

303 of 307 (goal 300) evaluable patients were enrolled on the prospective randomized trial between 2002 and 2006. Of these, 152 were assigned to receive CIMRT and 151 to receive HIMRT.

Gleason Score greater than or equal to 6 was required. Androgen deprivation was allowed.

Median follow-up for those alive was >67 months in both arms.

Patients were stratified by Gleason score, PSA, and use of long term androgen deprivation therapy use.

Primary endpoint included the ASTRO Biochemical Failure (BF) definition of 3 consecutive rises as well as Nadir+2 ng/mL definition and salvage therapy prior to biochemical failure.

The treatment arms were well balanced with respect to T-category, Gleason score, pretreatment initial PSA, use of androgen deprivation therapy (ADT) and length of ADT.

1/3 of patients were in the high-risk group and 45% received androgen deprivation.

Results

There were a total of 61 failures by the ASTRO definition of biochemical failure. There were no differences in any endpoint between the two arms in terms of efficacy of treatment for prostate cancer.

The 5-year cumulative incidence rates of BF were 21% for CIMRT, and 22% for HIMRT using ASTRO definition. Using Nadir + 2 definition for BF, there rates of BF were 15% for CIMRT vs 19% HIMRT. Rates for LRF/DM were 1.0% and 1.3% for CIMRT and HIMRT at 5 years.

There was no significant increase in Grade 2+ GI toxicity in this updated data. Cumulative incidence was 4.1% in CIMRT and 5.9% in HIMRT.

There was a significant increase in Grade 2+ GU toxicity with hypofractionated arm in this update. The grade 2 or higher toxicities for the CIMRT and HIMRT arms were 8.3% and 18.3% (statistically significant) for GU reactions. The toxicity consisted of incontinence, urgency, and frequency. Most were not repeated when patients were followed in time.

Author's Conclusions

With a median follow up of greater than 5 years, the efficacy of hypofractionated IMRT for the treatment of prostate cancer appears to be equivalent to conventional IMRT in this randomized trial at Fox Chase Cancer Center.

The GI toxicity for hypofractionated radiation was similar at 5 years to conventional IMRT.

In terms of GU toxicity, there was worse grade 2+ toxicity at 5 years with hypofractionation. This toxicity for hypofractionation is similar to other modalities.

Patients with an AUA score >10 had worse GU toxicity.

Hypofractionated IMRT is a reasonable option for men with intermediate to high risk prostate cancer.

Clinical Implications

Hypofractionated radiation has drawn significant attention for prostate cancer as it has the potential to take advantage of the low alpha/beta ratio for prostate cancer, it offers the convenience of decreased treatment times for patients, and it is more cost effective for the healthcare system.

The largest concern with increasing hypofractionation is the potential for late toxicity. This study revealed very low rates of late GI toxicity with no grade 3 toxicity seen. There were higher rates of GU toxicity seen in the hypofractionated arm; however, these toxicities were very closely associated with pre-treatment AUA and were rarely repeated.

Of note, patients with an AUA > 10 should be avoided for hypofractionation due to the increased risk of GU toxicity. Additionally, for future hypofractionation trials, it may be valuable to revise bladder and urethral constraints.

Several randomized trials, including this trial, have demonstrated the efficacy of hypofractionation with prostate cancer. In fact, within this trial, less failures were seen than anticipated. This leads to the question, "Are we using a fractionation with a large enough dose per fraction?" In fact, last year, Arcangeli et al (IJROBP 2010) published the results of a randomized trial from Italy evaluating the toxicity and efficacy of hypofractionated (62 Gy/20 fractions, 4 fractions per week) vs. conventional fractionation radiotherapy (80 Gy/40 fractions/8 weeks). They report that the hypofractionated arm had similar toxicity with improved biochemical failure rates.

Further follow up is needed to ensure there are not differences in late failures between the treatment arms.